2,3-Dihalogeno-6-trifluoromethylbenzene derivatives and processes for the preparation thereof

ABSTRACT

2,3-Dihalogeno-6-trifluoromethylbenzaldehydes of general formula (I) useful as intermediates for the preparation of fungicides for agricultural and horticultural use;a process for the preparation of the same; and process for preparing 2,3-dihalogeno-6-trifluoromethylbenzamidoximes of general formula (IV) from the above compounds, wherein X 1  and X 2  are each independently fluoro, chloro or bromo. ##STR1##

this is the U.S. National Stage Application of PCT/JP97/02,613 filedJul. 29, 1997 now WO98/04509 published Feb. 5, 1998.

FIELD OF THE INVENTION

The present invention is related to2,3-dihalogeno-6-trifluoromethylbenzaldehyde useful as intermediates forproducing agrohorticultural bactericides, a process for producing thesaid compounds, and a process for producing2,3-dihalogeno-6-trifluoromethylbenzamidoxime from the said compounds.

BACKGROUND ART

Known conventional methods to introduce a formyl group into an aromaticring are to react alkyl lithium, such as n-butyl lithium, withN,N-dimethylformamide (DMF) or N-phenyl-N-methylformamide, to reactalkyl lithium with formate, such as methyl formate, and the like.

For example, European Patent Laid-open specifications Nos. 125803 and174131 describe a method to react 2,5-difluorobenzotrifluoride withn-butyl lithium and N-phenyl-N-methylformamide. However, thisformylation reaction usually gives two reaction products, not beingselective.

In the case of the reaction of 3,4-dichlorobenzotrifluoride with n-butyllithium and DMF, 2,3-dichloro-5-trifluoromethylbenzaldehyde is the mainproduct, as described later.

In the Japanese Patent Laid-open No. Hei 3-5436 Gazette, compoundsrepresented by the general formula (Ia), which contain the compounds ofthis invention, are described. ##STR2##

Conventionally 2,3-dihalogeno-6-trifluoromethylbenzamidoximes have beenproduced via 2,3-dihalogeno-6-trifluoromethylbenzonitrile (refer toWO/19442 Gazette). However, this method had problems of low yield andlong reaction processes.

DISCLOSURE OF THE INVENTION

The present invention is directed to2,3-dihalogeno-6-trifluoromethylbenzaldehydes, an outstanding industrialprocess for producing the same, and an excellent industrial process forproducing 2,3-dihalogeno-6-trifluoromethylbenzamidoxime by using2,3-halogeno-6-trifluoromethylbenzaldehyde as a starting material.

The present invention is directed to

(1) the compounds represented by a general formula (I) ##STR3## whereinX¹ and X² are the same or different and each independently a fluorine,chlorine or bromine atom,

(2) a process for producing the compounds represented by the generalformula (I) ##STR4## wherein X¹ and X² are as defined above,characterized in that the compound is obtained by reacting a compoundrepresented by a general formula (II) ##STR5## wherein X¹ and X² are asdefined above, with n-butyl lithium and formate

and (3) a process for producing2,3-dihalogeno-6-trifluoromethylbenzamidoxime represented by a generalformula (IV) ##STR6## wherein X¹ and X² are as defined above,characterized in that the compound is obtained by oximating a compoundrepresented by the above general formula (I) to produce a compoundrepresented by a general formula (III) ##STR7## wherein X¹ and X² are asdefined above, then subsequently by amide oximating the said compound.

The process (2) of this invention is described below:

A 3,4-dihalogenobenzotrifluoride is reacted with an alkylated lithium,such as n-butyl lithium and formate, in solvents, while cooling at thetemperature of -30˜-70° C.

Solvents to be used in the reaction are not particularly restricted ifthey are inert, for example, ethers such as tetrahydrofuran (THF),dioxane and diethyl ether, aromatic hydrocarbons such as toluene andxylene, and saturated hydrocarbons such as hexane and pentane. Thesesolvents can be used alone or a mixture thereof.

The examples of formates used for the reaction are methyl formate, ethylformate, propyl formate, isopropyl formate, butyl formate, t-butylformate, phenyl formate and benzyl formate. The use of methyl formateand ethyl formate is particularly preferable due to easy handling andproduction cost.

As the 2,3-dihalogeno-6-trifluoromethylbenzaldehyde compounds of thisinvention, the following can be given:

1: 2,3-dichloro-6-trifluoromethylbenzaldehyde ¹ H-NMR (CDCl₃, δppm fromTMS): 7.64 (1H, d, J=8.5 Hz), 7.74 (1H, d, J=8.5 Hz), 10.44 (1H, s)

2: 2,3-difluoro-6-trifluoromethylbenzaldehyde ¹ H-NMR (CDCl₃, δppm fromTMS): 7.49 (1H, q, J=9.0 Hz), 7.61 (1H, dd, J=9.0 Hz, J=4.8 Hz), 10.39(1H, s)

3: 2,3-dibromo-6-trifluoromethylbenzaldehyde

4: 2-chloro-3-fluoro-6-trifluoromethylbenzaldehyde ¹ H-NMR (CDCl₃, δppmfrom TMS) 7.42 (1H, t, J=8.7 Hz), 7.72 (1H, dd, J=8.7 Hz, J=4.8 Hz),10.45 (1H, s)

5: 3-chloro-2-fluoro-6-trifluoromethylbenzaldehyde ¹ H-NMR (CDCl, δppmfrom TMS) 7.74 (1H, t, J=8.0 Hz), 7.57 (1H, d, J=8.0 Hz), 10.40 (1H, s)

6: 2-bromo-3-chloro-6-trifluoromethylbenzaldehyde

7: 2-bromo-3-fluoro-6-trifluoromethylbenzaldehyde

8: 3-bromo-2-chloro-6-trifluoromethylbenzaldehyde

9: 3-bromo-2-fluoro-6-trifluoromethylbenzaldehyde

The process (3) of this invention for producing2,3-halogeno-6-trifluoromethylbenzamide oximes from the above-mentionedbenzaldehydes is described below: The first process of this invention,the oximating reaction from a compound represented by the generalformula (I) to a compound represented by the general formula (III), is areaction with hydroxylamine in inert solvents. The hydroxylamine can bein the form of hydrochloride or sulfate. There are no particularrestrictions on solvents used for the reaction if they are inert.Examples are alcohols such as methanol, ethanol, propanol andisopropanol, water and acetonitrile. The reaction proceeds smoothlywithin the temperature range from room temperature to the boiling pointof the solvent used.

The second process, the amide oximating reaction from a compoundrepresented by the general formula (III) to a compound represented bythe general formula (IV), is a reaction with a halogenating agent ininert solvents to produce imidoyl halide (V) followed by a reaction withammonia.

There are no particular restrictions on solvents used for the reactionif they are inert. For example, in the halogenation process, halogenatedhydrocarbons, such as dichloromethane, chloroform, carbon tetrachlorideand 1,2-dichloroethane, can be used. In the process of amide oximation,examples are alcohols such as methanol, ethanol, propanol andisopropanol, water and acetonitrile.

Examples of halogenating agents include N-chlorosuccinimide,N-bromosuccinimide, chlorine, bromine, surfuryl chloride andhypochlorite. Ammonia can be used in the form of ammonia gas and analcohol solution, such as methanol and ethanol, of ammonia, and as wellas aqueous ammonia. The reaction proceeds smoothly within thetemperature range from -10° C. to the boiling point of the solvent used.

The production process of the present invention is described below:##STR8##

Compounds represented by the general formula (III) can be derived tobenzonitrile represented by a general formula (VI) ##STR9## wherein X¹and X² are as defined above, by reacting with acetic anhydride. Thereaction is usually carried out by heating a compound represented by thegeneral formula (III) in acetic anhydride under reflux. The compound isalso useful as an intermediate for agrochemicals.

In each case, the objective compounds can be obtained by usualpost-treatment after the reaction is completed. The structure of thecompounds of this invention was decided from IR, NMR, MASS and otheravailable means.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is further described in detail with reference tothe following examples. This invention is not restricted by theexamples.

EXAMPLE 1

Synthesis of 2,3-dichloro-6-trifluoromethylbenzaldehyde ##STR10##

54 g (0.25 mol) of 3,4-dichlorobenzotrifluoride was dissolved in 500 mlof anhydrous THF, and cooled down to -70° C. with dry ice/acetone. Tothe solution, 190 ml (0.3 mol) of hexane solution of n-butyl lithium wasadded dropwise over 45 minutes, while keeping the temperature at -70 °C. The reaction solution was matured for an hour at -70° C., then 30 g(0.5 mol) of methyl formate was dropped into the solution over 30minutes, while keeping the temperature at -70 ° C. After the reactionsolution was matured for an hour at -70° C., the temperature of thesolution was elevated to room temperature. The reaction solution waspoured into ice water and extracted with ether. The organic layerobtained was washed with water and then dried over anhydrous magnesiumsulfate. The solvent was distilled out under reduced pressure. Theresulting residue was distilled to give 47.3 g of oily product. Yield77% (purity 95%), 84˜94° C./3mmHg.

EXAMPLE 2

Example 1 was repeated except carrying out the reaction at -45° C. Yield(weight) 42.0 g, (yield 68.9%, purity 93%).

EXAMPLE 3

Synthesis of 2,3-difluoro-6-trifluoromethylbenzaldehyde ##STR11##

2.73 g (0.015 mol) of 3,4-difluorobenzotrifluoride was dissolved in 27ml of anhydrous THF, and cooled down to -70° C. with dry ice/acetone. Tothe solution, 9.4 ml (0.015 mol) of 1.6M hexane solution of n-butyllithium was slowly added dropwise, while keeping the temperature from-70° C. to -45 ° C. The reaction solution was matured for 2 hours at-45° C. Subsequently 1.8 g (0.03 mol) of methyl formate was added to thesolution dropwise over 30 minutes, while keeping the temperature at -45°C. After the reaction solution was matured for an hour at -45° C., thetemperature of the solution was elevated to room temperature. Thereaction solution was poured into ice water and extracted with ether.The organic layer obtained was washed with water and then dried overanhydrous magnesium sulfate. The solvent was distilled out under reducedpressure. The resulting residue was purified through silica gel columnchromatography to give 2.7 g of the title compound. Yield 85%, nD (20)1.4357.

2,3-Dichloro-6-trifluoromethylbenzaldehyde obtained in Examples 1 and 2,when used as a starting material, can be derived to2-fluoro-3-chloro-6-trifluoromethylbenzaldehyde and2,3-difluoro-6-trifluoromethylbenzaldehyde according to the methodsdescribed in Houben-Weyl, Methoden der Org. Chemie, Volume E3, page 350.The reaction is usually carried out using a fluoride, such as sodiumfluoride, potassium fluoride and cesium fluoride, in an inert solvent,such as sulfolane, dimethylsulfoxide and DMF, in the presence of acatalyst, if required, including crown ether, a phosphonium salt, suchas tetraphenylphosphonium bromide and tetrabutylphosphonium bromide, andan ammonium salt, such as tetramethylammonium chloride,tetraethylammonium chloride, tetrabutylammonium iodide and benzyltributylammonium chloride, within the temperature range from roomtemperature to the reflux temperature of the ##STR12##

COMPARATIVE EXAMPLE 1

Synthesis of 2,3-dichloro-5-trifluoromethylbenzaldehyde ##STR13##

57.3 g of 3,4-dichlorobenzotrifluoride was dissolved in 500 ml of driedtetrahydrofuran under nitrogen atmosphere and was cooled down to -78° C.To the resulting solution was dropped 200 ml of 1.6M hexane solution ofn-butyl lithium. After the solution was further stirred for about 1.5hours at the same temperature, 38.9 g of DMF was added dropwise into thereaction solution. After the completion of the addition, the temperatureof the reaction system was gradually elevated to room temperature, whilechecking the progress of the reaction. Ice water was added to thereaction solution to extract with ether. The extract was dried overanhydrous magnesium sulfate. The solvent was distilled under reducedpressure. The obtained oily product was distilled under reduced pressureto give 45.3 g of oily residue (bp. 70˜85° C./2 mmHg). The analysis ofthe purity of the obtained residue by gas chromatography revealed thatit was a mixture of 2,3-dichloro-5-trifluoromethylbenzaldehyde and2,3-dichloro-6-trifluoromethylbenzaldehyde at the ratio of 7:1.

The NMR data of 2,3-dichloro-5-trifluoromethylbenzaldehyde is asfollows:

¹ H-NMR (CDCl₃, δppm from TMS): 7.97 (1H, d), 8.11 (1H, d), 10.50 (1H,s)

EXAMPLE 4

(Synthesis of 2,3-dichloro-6-trifluoromethylbenzaldehyde oxime)##STR14##

4.86 g (0.02 mol) of 2,3-dichloro-6-trifluoromethylbenzaldehyde wasdissolved in 30 ml of ethanol. To the solution 2.78 g (0.04 mol) ofhydroxylamine hydrochloride was added to heat under reflux for an hour.The reaction solution was cooled down and poured into ice water. Theresulting solution was extracted with ethyl acetate. The organic layerwas washed with water and dried over anhydrous magnesium sulfate. Thesolvent was distilled under reduced pressure to give 5.0 g of the titlecompound. Yield 97%, mp. 102˜104° C.

EXAMPLE 5

(Synthesis of 2,3-difluoro-6-trifluoromethylbenzaldehyde oxime)##STR15##

9.0 g (42.8 mmol) of 2,3-difluoro-6-trifluoromethylbenzaldehyde wasdissolved in 50 ml of ethanol. 3.39 g (85.6 mmol) of hydroxylaminehydrochloride was added to the resulting solution to heat under refluxfor an hour. The reaction solution was cooled down, and poured into icewater. The solution was extracted with ethyl acetate. The organic layerwas washed with water and dried over anhydrous magnesium sulfate. Thesolvent was distilled under reduced pressure to give 9.4 g of the titlecompound. Yield 97.6%, mp. 111˜112° C.

EXAMPLE 6

(Synthesis of 2,3-difluoro-6-trifluoromethylbenzamidoxime) ##STR16##

2.25 g (10 mmol) of 2,3-difluoro-6-trifluoromethylbenzaldehyde oxime wasdissolved in 20 ml of chloroform. While cooling with ice water, 1.59 g(12 mmol) of N-chlorosuccinimide was added to the solution. After thetemperature of the solution was elevated to room temperature, thesolution was stirred for 2 hours. Compounds with low boiling point weredistilled under reduced pressure, then ether was added to the residue.The precipitated crystals were separated by filtration. The filtrate wasadded dropwise into 10 ml of ethanol solution containing 0.5 g (30 mmol)of ammonia and stirred for 30 minutes. The solvent was distilled underreduced pressure. The residue was extracted with ethyl acetate. Theorganic layer was washed with water and dried over anhydrous magnesiumsulfate. The solvent was distilled under reduced pressure to give 1.9 gof the title compound. Yield 79.2%, mp 105˜107° C.

EXAMPLE 7

(Synthesis of 2,3-difluoro-6-trifluoromethylbenzamidoxime) ##STR17##

3.5 g (15 mmol) of 2,3-difluoro-6-trifluoromethylbenzaldehyde oxime wasdissolved in 20 ml of chloroform. 2 g (30 mmol) of chlorine gas wasblown into the resulting solution over 30 minutes, while cooling withice water. The temperature of the reaction solution was elevated to roomtemperature and the solution was stirred further for 2 hours. Compoundswith low boiling point were distilled from the reaction solution underreduced pressure. The resulting residue was dropped into a mixedsolution of 4.6 g of 28% aqueous ammonia and 20 ml of ethanol, andstirred for 30 minutes. The reaction solution was concentrated underreduced pressure. The obtained residue was extracted with ethyl acetate.The organic layer was washed with water and dried over anhydrousmagnesium sulfate. The solvent was distilled under reduced pressure togive 2.72 g of the title compound. Yield 72.9%.

REFERENCE EXAMPLE 1

(Synthesis of 2,3-dichloro-6-trifluoromethylbenzonitrile) ##STR18##

5.0 g (19.3 mmol) of 2,3-dichloro-6-trifluoromethylbenzaldehyde oximewas dissolved in 20 ml of acetic anhydride. The resulting solution washeated under reflux for 4 hours. Excessive acetic anhydride wasdistilled from the reaction solution under reduced pressure. The residuewas dissolved with ethyl acetate. The obtained solution was washed withwater and dried over anhydrous magnesium sulfate. The solvent wasdistilled under reduced pressure. The obtained product was purified bydistillation to give 4.2 g of the title compound. Yield 90.3%, mp 53˜54°C.

REFERENCE EXAMPLE 2

(Synthesis of 2,3-difluoro-6-trifluoromethylbenzonitrile) ##STR19##

3.0 g (13.3 mmol) of 2,3-difluoro-6-trifluoromethylbenzaldehyde oximewas dissolved in 12 ml of acetic anhydride. The resulting solution washeated under reflux for 4 hours. Excessive acetic anhydride wasdistilled from the reaction solution under reduced pressure. The residuewas dissolved with ethyl acetate. The obtained solution was washed withwater and dried over anhydrous magnesium sulfate. The solvent wasdistilled under reduced pressure. The obtained product was purified bydistillation to give 2.33 g of the title compound. Yield 84.4%, mp98˜100° C./25 mmHg.

Industrial Use

As described in the above, the present invention is related to novel2,3-dihalogeno-6-trifluoromethylbenzene derivatives. The compounds ofthis invention are useful as intermediates for agrochemicals,pharmaceuticals, and particularly agrohorticultural bacteriocides. Withthe use of the methods of this invention,2,3-dihalogeno-6-trifluoromethylbenzaldehyde compounds and2,3-dihalogeno-6-trifluoromethylbenzamide oximes can be produced simplyand highly selectively with high yield.

What is claimed is:
 1. A process for producing2,3-dihalogeno-6-trifluoromethylbenzaldehyde represented by a formula(I) ##STR20## wherein X¹ and X² are the same or different and eachindependently represent a fluorine, chlorine or bromine atom, comprisingreacting a compound represented by a formula (II) ##STR21## wherein X¹and X² are as defined above with alkyl lithium and formate.
 2. Theprocess of claim 1 wherein the alkyl lithium is n-butyl lithium.
 3. Theprocess of claim 1 wherein the formate is methyl formate or ethylformate.